The Human Immunodeficiency Virus (HIV) transactivator of transcription (Tat) mediates at least two independent activities, a receptor-mediated triggering event at the cellular surface and an intracellular trans-activation activity that controls antigen-presenting cell (APC) differentiation. The receptor-mediated triggering event mediated by Tat is specific to APC, committing them for activation and differentiation into highly immunosuppressive antigen presenting cell regulatory macrophages (AReg) or into dendritic cells (DC) that stimulate specific cytotoxic T lymphocytes.
Antigen-presenting cells, macrophages and dendritic cells are critical in the pathogenesis or response to a variety of diseases, disorders and undesired immune responses. Tat triggers monocytes to differentiate into antigen-presenting macrophages expressing molecules that specifically suppress the immune response to the presented antigen(s). In autoimmune diseases, certain of the body's own endogenous molecules are incorrectly recognized as foreign, resulting in extensive inflammation and tissue damage. In one example, degradation of collagen type II into immunogenic peptides can trigger rheumatoid arthritis (RA) in animals and has been associated with human RA. Considerable research has centered on reducing the immune response to these proteins. The antigen-specific macrophage-induced suppression attributed to Tat can be applied to the reduction of the undesired immune response to foreign and endogenous molecules associated with inflammation and neurodegeneration.
Attempts to treat inflammation and autoimmune disorders have met with limited success. This is due, in part, to the fact that the etiology of inflammation and autoimmune disorders is a complex response based in part on the various inflammation-inducing molecules and the multitude of inflammation-mediating and -sensitizing molecules that appear to elicit inflammation via redundant mechanisms. Therefore, compounds, compositions, and methods that can treat inflammation, neurodegenerative disease, or an autoimmune disorder would be highly desirable.